TWI421248B - 作為plk抑制劑之嘧啶 - Google Patents
作為plk抑制劑之嘧啶 Download PDFInfo
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- TWI421248B TWI421248B TW094128434A TW94128434A TWI421248B TW I421248 B TWI421248 B TW I421248B TW 094128434 A TW094128434 A TW 094128434A TW 94128434 A TW94128434 A TW 94128434A TW I421248 B TWI421248 B TW I421248B
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- heteroaryl
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- 150000003230 pyrimidines Chemical class 0.000 title description 9
- 239000003112 inhibitor Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 128
- 239000000203 mixture Substances 0.000 claims description 90
- -1 methylamino, dimethylamino Chemical group 0.000 claims description 67
- 125000005843 halogen group Chemical group 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 150000001412 amines Chemical class 0.000 claims description 29
- 239000013543 active substance Substances 0.000 claims description 22
- 125000000304 alkynyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 229920006395 saturated elastomer Polymers 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000002619 bicyclic group Chemical group 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 108091000080 Phosphotransferase Proteins 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 102000020233 phosphotransferase Human genes 0.000 claims description 9
- 230000001028 anti-proliverative effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 239000000824 cytostatic agent Substances 0.000 claims description 4
- 230000001085 cytostatic effect Effects 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 230000007246 mechanism Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 231100000433 cytotoxic Toxicity 0.000 claims description 2
- 230000001472 cytotoxic effect Effects 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 252
- 238000000034 method Methods 0.000 description 180
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 134
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 129
- 239000002904 solvent Substances 0.000 description 123
- 239000000243 solution Substances 0.000 description 89
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 88
- 239000011541 reaction mixture Substances 0.000 description 85
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 210000004027 cell Anatomy 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 44
- 239000012074 organic phase Substances 0.000 description 43
- 238000004440 column chromatography Methods 0.000 description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 239000012043 crude product Substances 0.000 description 32
- 229920001296 polysiloxane Polymers 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 229920000159 gelatin Polymers 0.000 description 30
- 239000008273 gelatin Substances 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 22
- 235000019253 formic acid Nutrition 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- 239000003054 catalyst Substances 0.000 description 19
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 17
- 229910052763 palladium Inorganic materials 0.000 description 16
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- NBPIWQVZIWXXAE-UHFFFAOYSA-N 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 NBPIWQVZIWXXAE-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 235000011181 potassium carbonates Nutrition 0.000 description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 10
- 230000022131 cell cycle Effects 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 101710183160 Serine/threonine-protein kinase PLK1 Proteins 0.000 description 7
- 150000001448 anilines Chemical class 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000012876 carrier material Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012996 alamarblue reagent Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 230000000394 mitotic effect Effects 0.000 description 6
- 230000000269 nucleophilic effect Effects 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 6
- DNVUSPNLVWYALI-UHFFFAOYSA-N 4-[[4-[[2-(2-fluoroethyl)-1-methyl-3-oxo-1h-isoindol-4-yl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC1=NC=C(C(F)(F)F)C(NC=2C=3C(=O)N(CCF)C(C)C=3C=CC=2)=N1 DNVUSPNLVWYALI-UHFFFAOYSA-N 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 5
- 230000004668 G2/M phase Effects 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 5
- 238000006268 reductive amination reaction Methods 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 4
- PXRPHKYOQOMZGQ-UHFFFAOYSA-N 3-bromo-4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzoic acid Chemical compound BrC1=CC(C(=O)O)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 PXRPHKYOQOMZGQ-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- JGUGUBMVSNDFQX-UHFFFAOYSA-N 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 JGUGUBMVSNDFQX-UHFFFAOYSA-N 0.000 description 4
- ZPJBSWJZELXZKA-UHFFFAOYSA-N 7-amino-2,3-dihydroisoindol-1-one Chemical compound NC1=CC=CC2=C1C(=O)NC2 ZPJBSWJZELXZKA-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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-
2005
- 2005-08-17 US US11/206,703 patent/US7521457B2/en not_active Expired - Fee Related
- 2005-08-18 KR KR1020077004974A patent/KR101277506B1/ko not_active Expired - Fee Related
- 2005-08-18 AU AU2005276500A patent/AU2005276500B2/en not_active Ceased
- 2005-08-18 MX MX2007002055A patent/MX2007002055A/es active IP Right Grant
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- 2005-08-18 NZ NZ553632A patent/NZ553632A/en not_active IP Right Cessation
- 2005-08-18 DK DK05777896T patent/DK1781640T3/en active
- 2005-08-18 CA CA2573371A patent/CA2573371C/en not_active Expired - Fee Related
- 2005-08-18 ES ES05777896.1T patent/ES2532611T3/es not_active Expired - Lifetime
- 2005-08-18 CN CNA2005800359954A patent/CN101044137A/zh active Pending
- 2005-08-18 EP EP05777896.1A patent/EP1781640B1/de not_active Expired - Lifetime
- 2005-08-18 RU RU2007109870/04A patent/RU2404979C2/ru not_active IP Right Cessation
- 2005-08-18 WO PCT/EP2005/054089 patent/WO2006021544A1/de active Application Filing
- 2005-08-18 PL PL05777896T patent/PL1781640T3/pl unknown
- 2005-08-18 HU HUE05777896A patent/HUE025285T2/en unknown
- 2005-08-18 BR BRPI0514371-3A patent/BRPI0514371A/pt active Search and Examination
- 2005-08-19 TW TW094128434A patent/TWI421248B/zh not_active IP Right Cessation
- 2005-08-22 AR ARP050103502A patent/AR051195A1/es not_active Application Discontinuation
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2007
- 2007-01-03 ZA ZA200700084A patent/ZA200700084B/xx unknown
- 2007-02-19 IL IL181421A patent/IL181421A/en active IP Right Grant
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2009
- 2009-02-05 US US12/366,078 patent/US20090149438A1/en not_active Abandoned
- 2009-02-05 US US12/366,075 patent/US20090163465A1/en not_active Abandoned
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2010
- 2010-12-20 US US12/972,976 patent/US20110086842A1/en not_active Abandoned
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WO2000012485A1 (en) * | 1998-08-29 | 2000-03-09 | Astrazeneca Ab | Pyrimidine compounds |
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Also Published As
Publication number | Publication date |
---|---|
DK1781640T3 (en) | 2015-04-20 |
US20090149438A1 (en) | 2009-06-11 |
NZ553632A (en) | 2010-12-24 |
EP1781640A1 (de) | 2007-05-09 |
WO2006021544A1 (de) | 2006-03-02 |
ES2532611T3 (es) | 2015-03-30 |
EP1781640B1 (de) | 2015-01-07 |
CN101044137A (zh) | 2007-09-26 |
JP2008510691A (ja) | 2008-04-10 |
AU2005276500A1 (en) | 2006-03-02 |
US20090163465A1 (en) | 2009-06-25 |
TW200619218A (en) | 2006-06-16 |
US20060148800A1 (en) | 2006-07-06 |
AR051195A1 (es) | 2006-12-27 |
PL1781640T3 (pl) | 2015-06-30 |
RU2007109870A (ru) | 2008-11-10 |
CA2573371C (en) | 2013-02-19 |
MX2007002055A (es) | 2007-03-29 |
KR20070048757A (ko) | 2007-05-09 |
ZA200700084B (en) | 2008-02-27 |
KR101277506B1 (ko) | 2013-06-25 |
US7521457B2 (en) | 2009-04-21 |
HUE025285T2 (en) | 2016-03-29 |
CA2573371A1 (en) | 2006-03-02 |
BRPI0514371A (pt) | 2008-06-10 |
RU2404979C2 (ru) | 2010-11-27 |
IL181421A0 (en) | 2007-07-04 |
US20110086842A1 (en) | 2011-04-14 |
AU2005276500B2 (en) | 2012-05-10 |
JP5060294B2 (ja) | 2012-10-31 |
IL181421A (en) | 2015-05-31 |
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